Brain VDR Regulate Glucose Balance

我们对维生素D如何调节葡萄糖缺乏了解，这阻碍了它作为有效的糖尿病药物的使用。 疗法我们已经证明，维生素D可以在大脑中发挥作用，降低葡萄糖水平， 脑室旁下丘脑（PVH）内的VDR受体（VDR）对正常葡萄糖至关重要 肥胖动物体内的水平，而不是瘦的动物。然而，VDRPVH神经元的神经回路/功能， PVH VDR对膳食维生素D的反应，以及肥胖而非瘦状态下的潜在作用机制， 未知这就提出了关于维生素D受体如何调节葡萄糖平衡的基本问题。我们有 产生了在VDR阳性细胞中具有Cre重组酶表达的遗传小鼠模型（VDRCre）。这 为确定VDRPVH的功能、必要性和下游神经元靶点提供了一个极好的模型 神经元此外，利用其他遗传工具，我们可以确定PVH内的VDR是否是 饮食中维生素D对血糖的影响。最后，我们可以利用这些工具来确定机制 大脑中维生素D对葡萄糖调节的潜在体重特异性作用。该补助金的目的是 以确定大脑中维生素D对葡萄糖平衡的机制。我们假设VDR调节 葡萄糖水平通过不同的神经元回路和通过PVH神经元中的基因组效应。中央 将通过三个具体目标来检验假设：1）鉴定PVH VDR阳性的神经元机制 2）确定PVH VDR是否需要或足以用于葡萄糖中的饮食维生素D变化 体内平衡;和3）在肥胖模型中建立维生素D的葡萄糖保护作用的机制。 在目标1中，我们将使用化学遗传学，单细胞基因组学和免疫组织化学来确定 VDRPVH神经元的功能、身份和电路。在目标2中，我们将使用不同的饮食操作， 维生素D，以测试PVH VDR是否是高维生素D诱导的葡萄糖改善所必需的。此外，本发明还 我们将确定活性维生素D的中枢给药是否能克服低饮食的有害影响， 维生素D对葡萄糖平衡的影响在目标3中，我们将确定肥胖如何改变转录组和神经元 对活性维生素D（1，25 D3）的活化反应。此外，我们将确定VDR是否存在差异 在肥胖与瘦状态中的VDR表达或VDR+神经元数目。这项研究具有创新性，因为 它研究了一种新的神经元群体（VDRPVH）对葡萄糖耐量的功能，使用一种新的小鼠， 模型拟议的研究是有意义的，因为它有望确定新的范式来理解 维生素D的作用，以及可能确定一个新的电路在PVH与关键的葡萄糖调节 特性.这项研究的结果可能最终解释了临床试验中的一些差异， 维生素D作为一种疗法，并提供关键信息，以促进使用维生素D作为一种治疗剂。 总而言之，我设想这项建议的完成将使这项研究朝着以下长期目标发展： 了解如何利用维生素D作为2型糖尿病的有效疗法。

Our lack of understanding regarding how vitamin D regulates glucose prevents its use as an effective diabetes therapy. We have shown that vitamin D can act in the brain to lower glucose levels and that loss of vitamin D receptors (VDR) within the paraventricular hypothalamus (PVH) of the brain are critical for normal glucose levels in obese, but not lean, animals. However, the neurocircuitry/function of VDRPVH neurons, the role of the PVH VDR responding to dietary vitamin D, and mechanisms underlying effects in obese but not lean states are unknown. This raises basic questions regarding how vitamin D receptors mediate glucose balance. We have generated a genetic mouse model with Cre recombinase expression in VDR positive cells (VDRCre). This provides an excellent model to determine the function, necessity, and downstream neuronal targets of VDRPVH neurons. Additionally, utilizing other genetic tools, we can determine if VDR within the PVH are necessary for changes in blood glucose by dietary vitamin D. Last, we can utilize these tools to determine the mechanisms underlying weight-specific effects of vitamin D in the brain on glucose regulation. The objective of this grant is to determine the mechanisms of vitamin D in the brain on glucose balance. We hypothesize that VDR regulate glucose levels through distinct neuronal circuits and through genomic effects in PVH neurons. The central hypothesis will be tested by three specific aims: 1) identifying neuronal mechanisms for PVH VDR positive neurons; 2) determining if PVH VDR are required or sufficient for dietary-vitamin D changes in glucose homeostasis; and 3) establishing mechanisms for the glucose-protective effect of vitamin D in an obese model. In Aim 1, we will use chemogenetics, single-cell genomics, and immunohistochemistry to determine the function, identity, and circuitry of VDRPVH neurons. In Aim 2, we will use different dietary manipulations of vitamin D to test if PVH VDR are necessary for high-vitamin D induced glucose improvements. Additionally, we will determine if central administration of active vitamin D can overcome deleterious effects of low dietary vitamin D on glucose balance. In Aim 3, we will determine how obesity alters the transcriptomic and neuronal activation response to active vitamin D (1,25D3). Additionally, we will determine if there are differences in VDR expression or VDR+ neuronal number in obese vs. lean states. The research proposed is innovative, because it investigates the function of a novel neuronal population (VDRPVH) on glucose tolerance, using a novel mouse model. The proposed research is significant because it is expected to identify new paradigms to understand vitamin D action, as well as possibly identifying a novel circuit in the PVH with critical glucose-regulating properties. Results from this research may ultimately explain some of the variance in clinical trials utilizing vitamin D as a therapy and provide critical information to advance the use of vitamin D as a therapeutic agent. Altogether, I envision that the completion of this proposal will move this research towards the long-term goal of understanding how to utilize vitamin D as an effective therapy for type 2 diabetes.